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Thr92Ala-D2 polimorphism and behavior

Abstract

T4 enters the cells through the transporters expressed in the plasma membrane where will be activated to T3 by type 2 deiodinase (D2). T3 then diffuses to the nucleus to interact with its receptors, the TRs, modulating gene transcription. Approximately 12 to 36% of the population presents polymorphism for D2 (Thr92Ala-D2) that correlates positively with intellectual deficiency, bipolarity, and psychosis. Our working hypothesis contemplates the possibility that the Thr92Ala-D2 mutation leads to important behavioral changes. Therefore, the long-term objective of this study is to evaluate the impact of the Thr92Ala-D2 mutation on the behavior of mice. Our hypothesis is based on a recent study published by Prof. Antonio Bianco, our collaborator, demonstrating that Thr92AlaD2 accumulates in the cell and causes stress in the endoplasmic reticulum, besides modifying the cellular transcriptome of signaling pathways possibly involved in the modulation of the cognition. In addition, preliminary studies with the mouse carrying the polymorphism showed that the animal has a decrease in motivational behavior and short-term memory impairment. Our methodological approach will involve the evaluation of behavior using the following tests: open field to evaluate locomotion; elevated plus maze to evaluate anxiety; Barnes's labyrinth to assess visuospatial memory; object recognition to evaluate declarative memory and social recognition to evaluate social memory. After the behavioral evaluation, the animals will be sacrificed for gene expression. evaluation in the hippocampus, amygdala and prefrontal cortex using microarray technique. Genes that were found altered in the microarray analysis will be measured real-time PCR. Also, other genes of interest will also be evaluated by real-time PCR. The analysis of these parameters will allow the understanding of the mechanisms involved in the behavioral changes induced by Thr92AlaD2. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ALICE BATISTUZZO; MIRIAM OLIVEIRA RIBEIRO. Clinical and subclinical maternal hypothyroidism and their effects on neurodevelopment, behavior and cognition. ARCHIVES OF ENDOCRINOLOGY METABOLISM, v. 64, n. 1, p. 89-95, Fev. 2020. Web of Science Citations: 0.
BIANCO, ANTONIO C.; DUMITRESCU, ALEXANDRA; GEREBEN, BALAZS; RIBEIRO, MIRIAM O.; FONSECA, TATIANA L.; FERNANDES, GUSTAVO W.; BOCCO, BARBARA M. L. C. Paradigms of Dynamic Control of Thyroid Hormone Signaling. ENDOCRINE REVIEWS, v. 40, n. 4, p. 1000-1047, AUG 2019. Web of Science Citations: 4.
JO, SUNGRO; FONSECA, TATIANA L.; BOCCO, BARBARA M. L. C.; FERNANDES, GUSTAVO W.; MCANINCH, ELIZABETH A.; BOLIN, ANAYSA P.; DA CONCEICAO, RODRIGO R.; WERNECK-DE-CASTRO, JOAO PEDRO; IGNACIO, DANIELE L.; EGRI, PETER; NEMETH, DOROTTYA; FEKETE, CSABA; BERNARDI, MARIA MARTHA; LEITCH, VICTORIA D.; MANNAN, NAILA S.; CURRY, KATHARINE F.; BUTTERFIELD, NATALIE C.; BASSETT, J. H. DUNCAN; WILLIAMS, GRAHAM R.; GEREBEN, BALAZS; RIBEIRO, MIRIAM O.; BIANCO, ANTONIO C. Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain. Journal of Clinical Investigation, v. 129, n. 1, p. 230-245, JAN 2 2019. Web of Science Citations: 11.

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